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Calpains and skeletal muscle function

R.M. Murphy and G.D. Lamb, Department of Zoology, La Trobe University, Melbourne, VIC 3086, Australia.

Skeletal muscle fibres contain ubiquitous (μ-calpain and m-calpain) and muscle-specific (calpain-3), Ca2+-dependent proteases. Their physiological roles are not well understood, although ubiquitous calpains have been associated with apoptosis and myogenesis and calpain-3 has been suggested to be involved in sarcomeric remodeling. A defect in the expression of calpain-3 results in limb-girdle muscular dystrophy type 2A. Contrary to the dogma published from biochemical experiments that described calpain-3 as undergoing spontaneous autolysis (and hence activation) (Sorimachi et al., 2006), we have shown that this protease is stable unless exposed to [Ca2+] above resting physiological levels (> 50 nM). Our work has characterized the Ca2+- and time-dependencies of μ-calpain and calpain-3 in muscle homogenates, importantly with physiological ionic conditions preserved. During normal activity, skeletal muscle undergoes frequent episodes of high intracellular [Ca2+] and to understand how calpains are regulated during such periods, we have investigated various properties (such as diffusibility, binding and autolysis) of μ-calpain and calpain-3 using mechanically-skinned single fibres (Murphy, Venburg & Lamb, 2006). In addition, we have seen that overall the calpains were found not to be activated immediately following sprint, endurance or eccentric exercise in healthy human subjects (Murphy, Snow & lamb, 2006; Murphy et al., 2007). Notably, we found that a substantial proportion of calpain-3, but not μ-calpain, was activated 24 h after the eccentric exercise bout, which could possibly be explained by the small but sustained increase in intracellular [Ca2+] that occurs following eccentric contractions (Lynch, Fary & Williams, 1997) being both high and long enough to result in calpain-3 activation.

Sorimachi H, Toyama-Sorimachi N, Saido TC, Kawasaki H, Sugita H, Miyasaka M, Arahata K, Ishiura S, Suzuki K. (1993) Journal of Biological Chemistry, 268: 10593-605.

Murphy RM, Verburg E, Lamb GD. (2006) Journal Physiology, 576: 595-612.

Murphy RM, Snow RJ, Lamb GD. (2006) American Journal of Physiology, 290: C116-122.

Murphy RM, Goodman CA, McKenna MJ, Bennie J, Leikis M, Lamb GD. (2007) Journal of Applied Physiology, 103: 926-31.

Lynch GS, Fary CJ, Williams DA. (1997) Cell Calcium, 22: 373-83.